Analyzing biological rhythms in clinical trials

BackgroundThe human body exhibits a variety of biological rhythms. There are patterns that correspond, among others, to the daily wake / sleep cycle, a yearly seasonal cycle and, in women, the menstrual cycle. Sine/cosine functions are often used to model biological patterns for continuous data, but this model is not appropriate for analysis of biological rhythms in failure time data.MethodsWe consider a method appropriate for analysis of biological rhythms in clinical trials. We present a method to provide an estimate and confidence interval of the time when the minimum hazard is achieved. A motivating example from a clinical trial of adjuvant of pre-menopausal breast cancer patients provides an important illustration of the methodology in practice.ResultsAdapting the Cosinor method to the Weibull proportional hazards model is proposed as useful way of modeling the biological rhythm data. It presents a method to estimate the time that achieves the minimum hazard along with its associated confidence interval. The application of this technique to the breast cancer data revealed that the optimal day for pre-resection incisional or excisional biopsy of 28-day cycle (i.e. the day associated with the lowest recurrence rate) is day 8 with 95% CI 5–10. We found that older age, fewer positive nodes, smaller tumor size, and experimental treatment are important prognostic factors of longer relapse-free survival.ConclusionsThe analysis of biological/circadian rhythms is usually handled by Cosinor rhythmometry method. However, in FTD this is simply not possible. In this case, we propose to adapt the Cosinor method to the Weibull proportional hazard model. The advantage of the proposed method is its ability to model survival data. This method is not limited to breast cancer data, and may be applied to any biological rhythms linked to right censored data.     

Evaluation of coexistence of the Human Herpesvirus type 8 (HHV‐8) infection and pemphigus

Background Human Herpesvirus type 8 (HHV‐8) is a new member of the herpes virus family, first found in the tissue of acquired immune deficiency syndrome (AIDS)‐related Kaposi’s sarcoma. Environmental factors including viral infection may play a role in the onset and/or development of pemphigus. Some studies based on polymerase chain reaction findings suggest an association between HHV‐8 and pemphigus. The aim of this study is investigation of the association of pemphigus with HHV‐8 and the relationship between inflammatory and acantholytic cells with HHV‐8 infection. Methods Tissue‐extracted DNA from 41 paraffin‐embedded skin tissues from patients first presenting with pemphigus was tested using nested PCR for the presence of HHV‐8. A total of 37 cases had pemphigus vulgaris (PV) and 4 patients had pemphigus foliaceus (PF). For our control group, normal skin of 21 cosmetic surgery patients were included. Furthermore, microscopic slides with H&E staining were evaluated for the number of inflammatory and acantholytic cells per microscopic field. Results Skin lesions from 13 of 37 patients (35.1%) with PV and 2 of 4 cases (50%) with PF were positive for HHV‐8 DNA. All specimens in our control group were negative for this virus. Conclusion HHV‐8 infection might be a contributing factor in the initiation or development of pemphigus.     

Depression,anxiety, and fear of COVID-19 in patients with multiple sclerosis in pandemic era: a cross-sectional study

Neurological Sciences - Depression and anxiety are the two important factors determining quality of life of patients with multiple sclerosis (PWMS). In COVID-19 pandemic era, several factors can...     

Role of the vulnerable elders survey-13 screening tool in predicting treatment plan modification for older adults with cancer

Background: The Vulnerable Elders Survey (VES-13) is commonly used to identify older patients who may benefit from Comprehensive Geriatric Assessment (CGA) prior to cancer treatment. The optimal cut point of the VES-13 to identify those whose final oncologic treatment plan would change after CGA is unclear. We hypothesized that patients with high positive VES-13 scores (7–10)have a higher likelihood of a change in treatment compared to low positive scores (3–6).Methods: Retrospective review of a customized database of all patients seen for pre-treatment assessment in an academic geriatric oncology clinic from June 2015 to June 2019. Various VES-13 cut points were analyzed to identify those individuals whose treatment was modified after CGA. Area under the curve (AUC) was calculated and subgroups of patients treated locally or systemically were also examined to determine if performance varied by treatment modality.Results: We included 386 patients with mean age 81, 58% males. Gastrointestinal cancer was the most common site (31%) and 60% were planned to receive curative treatment. The final treatment plan was modified in 59% overall, with 52.7% modified with VES-13 scores 7–10, 50.8% with scores 3–6 and 28.1% with scores <3 (P = 0.002). VES-13 performance in predicting treatment modification was similar for cut points 3 (AUC 0.58), 4 (0.59), 5 (0.59), and 6 (0.59) and in those considering local treatment vs. chemotherapy.Conclusions: A positive VES-13 score was associated with final oncologic treatment plan modification. A high positive score was not superior to the conventional cut point of ≥3.     

Impact of various culture conditions on ex vivo expansion of polyclonal T cells for adoptive immunotherapy

Currently, adoptive immunotherapy is considered as one of the leading treatments in cancer. Successful adoptive immunotherapy depends on producing large numbers of desired T cells ex vivo for infusion. This requires an effective protocol for maximum functional T‐cell expansion while keeping the time and costs to a minimum. Current T‐cell expansion protocols are diverse in their methodology, and a universal protocol of expansion is wanting. Also, new findings regarding T‐cell biology, signaling, and activation have reshaped the strategies of T‐cell propagation over the years, introducing new ways to expand T cells. Here, we reviewed different conditions for blood‐derived polyclonal T‐cell expansion so as to elucidate the influential factors of T‐cell expansion and their efficacy.     

Ca2+ influx through T- and L-type Ca2+ channels have different effects on myocyte contractility and induce unique cardiac phenotypes

T-type Ca(2+) channels (TTCCs) are expressed in the developing heart, are not present in the adult ventricle, and are reexpressed in cardiac diseases involving cardiac dysfunction and premature, arrhythmogenic death. The goal of this study was to determine the functional role of increased Ca(2+) influx through reexpressed TTCCs in the adult heart. A mouse line with cardiac-specific, conditional expression of the alpha1G-TTCC was used to increase Ca(2+) influx through TTCCs. alpha1G hearts had mild increases in contractility but no cardiac histopathology or premature death. This contrasts with the pathological phenotype of a previously studied mouse with increased Ca(2+) influx through the L-type Ca(2+) channel (LTCC) secondary to overexpression of its beta2a subunit. Although alpha1G and beta2a myocytes had similar increases in Ca(2+) influx, alpha1G myocytes had smaller increases in contraction magnitude, and, unlike beta2a myocytes, there were no increases in sarcoplasmic reticulum Ca(2+) loading. Ca(2+) influx through TTCCs also did not induce normal sarcoplasmic reticulum Ca(2+) release. alpha1G myocytes had changes in LTCC, SERCA2a, and phospholamban abundance, which appear to be adaptations that help maintain Ca(2+) homeostasis. Immunostaining suggested that the majority of alpha1G-TTCCs were on the surface membrane. Osmotic shock, which selectively eliminates T-tubules, induced a greater reduction in L- versus TTCC currents. These studies suggest that T- and LTCCs are in different portions of the sarcolemma (surface membrane versus T-tubules) and that Ca(2+) influx through these channels induce different effects on myocyte contractility and lead to distinct cardiac phenotypes.     

The diagnostic accuracy of serologic markers in children with IBD: the West Virginia experience

GOAL: To assess the sensitivity/specificity of the serologic markers: perinuclear antineutrophil cytoplasmic antibody (pANCA) and anti-saccharomyces cerevisiae antibody (ASCA) in children diagnosed with inflammatory bowel disease (IBD), living in West Virginia. BACKGROUND: In recent years, serologic markers have been used to differentiate between CD and UC diseases in children. The clinical usefulness of these markers in children was restricted by their low sensitivity and specificity. Racial and ethnic diversity may alter the accuracy of these markers in children. The demographic homogeneity of the West Virginia population may offer a better clinical setup to reassess the utility of those markers in children with IBD. STUDY: A retrospective analysis of all the charts of children diagnosed with IBD was performed at the gastroenterology clinics of Marshall University, Huntington, WV; and West Virginia University, Charleston Division, Charleston, WV. The diagnosis of IBD was established according to clinical, radiologic, and endoscopic data. Laboratory data and serum markers were recorded, and their accuracy to diagnose UC or CD was assessed. RESULTS: A total of 101 charts were reviewed, of which only 90 (89%) included serologic markers and were considered for further analysis. Disease distribution included: UC-41, CD-44, and indeterminate colitis (IC)-7 (2 patients changed diagnosis after colectomy). Serum antibody pANCA had a sensitivity of 73% and specificity of 84% for UC, but only 16% and 35% for CD, respectively. Serum antibody ASCA had a sensitivity of 58% and specificity of 92% for CD, but only 7% and 49% for UC, respectively. The outer membrane porin to Escherichia coli antibody (anti-OmpC) was available in 54 (59%) children and demonstrated a very poor sensitivity for both diseases (sensitivity<11%). CONCLUSION: Despite our homogeneous patient population, pANCA and ASCA antibodies had an inadequate sensitivity/specificity for children with UC or CD. Those antibodies were not useful for our small number of patients with IC.